Endothelin Receptors Expressed by Immune Cells Are Involved in Modulation of Inflammation and in Fibrosis: Relevance to the Pathogenesis of Systemic Sclerosis

open13noEndothelin-1 (ET-1) plays a pivotal role in vasoconstriction, fibrosis, and inflammation, the key features of systemic sclerosis (SSc). ET-1 receptors (ETA and ETB) are expressed on endothelial cells, smooth muscle cells, and fibroblasts, but their presence on immune cells has not been deeply investigated so far. Endothelin receptors antagonists such as bosentan have beneficial effects on vasoconstriction and fibrosis, but less is known about their potential anti-inflammatory effects. We studied the expression of ET-1 receptors on immune cells (T and B lymphocytes, monocytes, and neutrophils) and the link between ET-1 and inflammation in patients with SSc. We show here that ET-1 exerts a proinflammatory effect in CD4+ T cells, since it induces an increased IFN-γ production; preincubation with antagonists of both receptors reduces IFN-γ production. Moreover, following ET-1 stimulation, neutrophils produce proinflammatory mediators, thus amplifying the effects of activated CD4+ T cells. Our data indicate that ET-1 system is involved in the pathogenesis of inflammation and fibrosis typical of SSc, through the activation of T lymphocytes and neutrophils and the consequent release of proinflammatory and profibrotic cytokines. These findings suggest that dual ET-1 receptors antagonist therapy, besides its effect on vasculopathy, has a profound impact on the immune system favouring antiinflammatory and antifibrogenic effects.openElisa, Tinazzi; Antonio, Puccetti; Giuseppe, Patuzzo; Alessandro, Barbieri; Giuseppe, Argentino; Federico, Confente; Marzia, Dolcino; Ruggero, Beri; Giacomo, Marchi; Andrea, Ottria; Daniela, Righetti; Mariaelisa, Rampudda; Claudio, LunardiTinazzi, Elisa; Puccetti, Antonio; Patuzzo, Giuseppe; Barbieri, Alessandro; Argentino, Giuseppe; Confente, Federico; Dolcino, Marzia; Beri, Ruggero; Marchi, Giacomo; Ottria, Andrea; Righetti, Daniela; Rampudda, Mariaelisa; Lunardi, Claudi

Anti-SAE antibodies in autoimmune myositis: Identification by unlabelled protein immunoprecipitation in an Italian patient cohort.

Myositis specific autoantibodies (MSAs) are useful in the diagnosis of idiopathic inflammatory myopathies and in the definition of disease subsets. The aim of this study was to set up an unlabelled protein immunoprecipitation technique for MSA identification in the sera of myositis patients, in order to identify and investigate new antibody reactivity, undetectable by currently used methods. Sera of 183 patients with connective tissue diseases (75 adult dermatomyositis, 12 juvenile dermatomyositis, 43 polymyositis, 53 other connective tissue diseases) and 30 healthy controls were screened by an in-house procedure of unlabelled protein immunoprecipitation. In the same sera MSAs and myositis associated antibodies were determined by immunoblotting and immunoprecipitation for RNA. The analytical specificity of unlabelled protein immunoprecipitation was demonstrated by testing reference sera with known antibody reactivity. Sera from five patients, affected with dermatomyositis (5/75=7%), immunoprecipitated two proteins of 40 and 90kDa apparent molecular weights respectively, consistent with the subunits of the small ubiquitin like modifier activating enzyme heterodimer (SAE1/SAE2). The identity of putative SAE immunoprecipitated proteins was confirmed by immunoblotting on immunoprecipitates using commercial monospecific antibodies to SAE1 and SAE2. Major clinical features were compared between anti-SAE positive and negative patients. Interestingly, anti-SAE positive patients had mainly skin and muscle manifestations while dysphagia, interstitial lung disease, arthritis and constitutional symptoms were absent. Unlabelled protein immunoprecipitation is a specific analytical approach, appropriate for the identification of the recently described anti-SAE autoantibody. We confirmed the role of anti-SAE antibody as marker of dermatomyositis

Preventive strategies in systemic lupus erythematosus

Despite the improvement of systemic lupus erythematosus (SLE) survival observed in the last decades, the long-term prognosis of these patients remains poor mainly due to complications of the disease and/or of its treatment. Therefore, in order to improve SLE prognosis, we should try to avoid long-term complications by adopting, early in the disease course, some strategies directed to prevent infections, atherosclerosis and cancer. Moreover, since it has been shown that autoantibodies appear before clinical manifestations in SLE, the question of whether or not asymptomatic individuals with a reliable positive serology should be treated arises. Other than advising these individuals to avoid sun exposure, drugs implicated in drug-induced lupus and cigarette smoking, the use of vitamin D and hydroxychloroquine could be considered. Finally, early SLE diagnosis has led to a modification of disease clinical spectrum at disease onset with an increased frequency of mild disease manifestations over severe ones. Thus great effort should be made in order to identify early in the disease course risk factors for the development of severe SLE manifestations. Finally patients with mild disease carrying factors predictive of severe manifestations should be treated more aggressively than we have done up to now

Mycophenolate mofetil in lupus glomerulonephritis: effectiveness and tolerability.

Mycophenolate mofetil (MMF) is an immunosuppressive agent initially used in the treatment of transplant recipients. MMF has been used in renal, heart, and liver transplantation, where it seems more effective than other immunosuppressive regimens in reducing the incidence of acute rejection episodes. MMF has a variety of immunosuppressive effects, including selective suppression of T and B lymphocyte proliferation, and has been more recently used in many autoimmune inflammatory conditions. Systemic lupus erythematosus (SLE) is an autoimmune disease that can potentially involve any organ or system of the human body. Glomerulonephritis (GLN) has been recognized as the most frequent severe manifestation of SLE, leading to poor long-term prognosis. In the treatment of lupus GLN, several therapeutic approaches, all including immunosuppressive drugs, such as cyclophosphamide, azathioprine, or cyclosporine A, have been used. The short- and long-term toxicity of these drugs limits their use in a substantial number of patients. Over the last few years, MMF has emerged as an alternative therapeutic regimen in lupus GLN, mainly for patients refractory to other therapies. These studies have shown that it is highly effective and generally well tolerated

Overlap connective tissue disease syndromes.

Overlap Syndromes (OSs) have been defined as entities satisfying classification criteria of at least two connective tissue diseases (CTDs) occurring at the same or at different times in the same patient. CTDs include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), polymyositis/dermatomyositis (PDM), and Sj\uf6gren syndrome (SS). Every combination between these disorders has been reported. In some OS a specific autoantibody has been indentified, supporting the hypothesis that these syndromes are not a mere association of two or more CTD in the same patient, but a well defined clinical entity with specific clinical characteristics. As an example, anti-t-RNA synthetase syndrome is characterized by the presence of anti-t-RNA synthetase antibodies. Notably, clinical manifestations observed in OS may be different from those observed in the single CTD. The treatment of OS is mainly based on the use of corticosteroids and immunosuppressants. Biologic drugs, i.e. anti-TNF\u3b1 or anti-CD20 monoclonal antibodies, have been recently introduced as alternative treatments in refractory cases. Moreover, there are some concerns with the use of anti-TNF agents in patients with systemic autoimmune diseases due to the risk of triggering disease exacerbations. In this paper the most frequent OS are described with a special focus on the specific immunologic and clinical aspects. Furthermore, some personal data on anti-t-RNA synthetase syndrome and rhupus syndrome are reported

The olfactory function is impaired in patients with idiopathic inflammatory myopathies.

The aim of our study was to analyze olfactory function in patients with idiopathic inflammatory myopathies (IIM). We performed a case-control study on 60 IIM patients (48 females and 12 males) and 60 healthy controls (HC) recruited by the best friend method, matched for age, sex and lifestyle. Olfactory function was analyzed by "Sniffin' sticks test" and expressed through a score (TDI), indicating normosmia (TDI > 30), hyposmia (TDI 15-30) and anosmia (TDI < 15). Mood was investigated by Beck depression inventory (BDI) test. Statistic was performed using SPSS package. Mean \ub1 SD TDI was significantly reduced in patients versus HC (26.8 \ub1 5.2 vs. 31.4 \ub1 3.5, p < 0.001). Anosmia was detected in two patients (3.3 %) and no HC, hyposmia in 41 patients and 14 HC (68.3 vs. 23.3 %, p < 0.0001) and normosmia in 17 patients and 48 HC (28.3 vs. 76.6 %, p < 0.0001). In the multivariate analysis carried out in the pool population of patients and HC, low TDI score was associated with age 6550 years (p < 0.0001), disease status (p < 0.0001) and high BDI (p = 0.007). When adjusting for BDI, disease status was still associated with low TDI (p = 0.037). In IIM, TDI was lower in subjects aged 6550 years (p = 0.008) and in patients who were taking corticosteroids (p < 0.0001). In the multivariate analysis carried out in IIM patients, low TDI was associated with age 6550 years (p = 0.001) and prednisone intake (p < 0.0001). The olfactory function is impaired in IIM patients. An underlying immune-mediated mechanism is conceivable, yet a possible interference due to age, steroid intake and depression should be considered

Endothelin Receptors Expressed by Immune Cells Are Involved in Modulation of Inflammation and in Fibrosis: Relevance to the Pathogenesis of Systemic Sclerosis

Endothelin-1 (ET-1) plays a pivotal role in vasoconstriction, fibrosis, and inflammation, the key features of systemic sclerosis (SSc). ET-1 receptors (ETA and ET(B)) are expressed on endothelial cells, smooth muscle cells, and fibroblasts, but their presence on immune cells has not been deeply investigated so far. Endothelin receptors antagonists such as bosentan have beneficial effects on vasoconstriction and fibrosis, but less is known about their potential anti-inflammatory effects. We studied the expression of ET-1 receptors on immune cells (T and B lymphocytes, monocytes, and neutrophils) and the link between ET-1 and inflammation in patients with SSc. We show here that ET-1 exerts a proinflammatory effect in CD4+ T cells, since it induces an increased IFN-γ production; preincubation with antagonists of both receptors reduces IFN-γ production. Moreover, following ET-1 stimulation, neutrophils produce proinflammatory mediators, thus amplifying the effects of activated CD4+ T cells. Our data indicate that ET-1 system is involved in the pathogenesis of inflammation and fibrosis typical of SSc, through the activation of T lymphocytes and neutrophils and the consequent release of proinflammatory and profibrotic cytokines. These findings suggest that dual ET-1 receptors antagonist therapy, besides its effect on vasculopathy, has a profound impact on the immune system favouring antiinflammatory and antifibrogenic effects

Endothelin Receptors Expressed by Immune Cells Are Involved in Modulation of Inflammation and in Fibrosis: Relevance to the Pathogenesis of Systemic Sclerosis

Endothelin-1 (ET-1) plays a pivotal role in vasoconstriction, fibrosis, and inflammation, the key features of systemic sclerosis (SSc). ET-1 receptors (ETA and ET(B)) are expressed on endothelial cells, smooth muscle cells, and fibroblasts, but their presence on immune cells has not been deeply investigated so far. Endothelin receptors antagonists such as bosentan have beneficial effects on vasoconstriction and fibrosis, but less is known about their potential anti-inflammatory effects. We studied the expression of ET-1 receptors on immune cells (T and B lymphocytes, monocytes, and neutrophils) and the link between ET-1 and inflammation in patients with SSc. We show here that ET-1 exerts a proinflammatory effect in CD4+ T cells, since it induces an increased IFN-\u3b3 production; preincubation with antagonists of both receptors reduces IFN-\u3b3 production. Moreover, following ET-1 stimulation, neutrophils produce proinflammatory mediators, thus amplifying the effects of activated CD4+ T cells. Our data indicate that ET-1 system is involved in the pathogenesis of inflammation and fibrosis typical of SSc, through the activation of T lymphocytes and neutrophils and the consequent release of proinflammatory and profibrotic cytokines. These findings suggest that dual ET-1 receptors antagonist therapy, besides its effect on vasculopathy, has a profound impact on the immune system favouring antiinflammatory and antifibrogenic effects